None listed
Conditions
Brief summary
The purpose of Part 1 of the study is determine if DSM265 is safe, how it makes people feel and how the body absorbs, processes and gets rid of DSM265 (study drug), in single, increasing oral doses of DSM265 in healthy subjects for the treatment of malaria. This trial is to be conducted under the Australian Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN).
Interventions
This is essentially a single centre, double-blind, randomised, placebo-controlled, ascending dose study in healthy subjects.
This study is divided into three parts.
The first part comprises of single dose cohorts to assess safety, pharmacokinetics, and the maximum tolerated dose, was well as an assessment of the food effect of DSM265.
The first single ascending dose (SAD) Part 1 of the study will involve up to seven cohorts for the single dose treatment (8 subjects per cohort for cohorts 1
This is essentially a single centre, double-blind, randomised, placebo-controlled, ascending dose study in healthy subjects. This study is divided into three parts. The first part comprises of single dose cohorts to assess safety, pharmacokinetics, and the maximum tolerated dose, was well as an assessment of the food effect of DSM265. The first single ascending dose (SAD) Part 1 of the study will involve up to seven cohorts for the single dose treatment (8 subjects per cohort for cohorts 1 - 6. 10 subjects for Cohort 4 and where the same 10 subjects will be used for Cohort 7. There will be at least a 7 day wash-out period between doses for cohorts 4 and 7. The mode of administration is an oral solution. As this part is an ascending dose study, the actual dose for the subsequent cohorts will be determined after review of safety and PK data from the first 3 cohorts. Cohort 1: 6 subjects will receive 25 mg DSM265; 2 subjects placebo; Cohort 2: 6 subjects will receive 75 mg DSM265; 2 subjects placebo; Cohort 3: 6 subjects will receive 150 mg DSM265; 2 subjects placebo; Cohorts 4 (fasted state) and 7 (fed state): 8 subjects will receive x mg DSM265; 2 subjects placebo. Cohort 5: 6 subjects will receive xx mg DSM265; 2 subjects placebo; Cohort 6: 6 subjects will receive xxx mg DSM265; 2 subjects placebo.
Sponsors
CPR Pharma Services
Study design
Allocation
Randomised controlled trial
Intervention model
Other
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed. 2. Healthy male and female (of non-childbearing potential) subjects age 18 to 55 years in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening. a. Women are considered post-menopausal and not of child bearing potential if they have had at least 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels at the local laboratory levels for post-menopause; or have had surgical bilateral oophorectomy or bilateral salpingectomy (with or without hysterectomy) at least six months ago. Women on oral contraceptives are to be excluded from the study, also women who have had a tubal ligation. 3. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three (3) minutes and again when required after three (3) minutes in the standing position. Investigators can be guided by the following ranges: a. oral body temperature between 35.0-37.5 degrees celcius b. systolic blood pressure, 90-140 mm Hg c. diastolic blood pressure, 50-90 mm Hg d. pulse rate, 40-90 bpm 4. When blood pressure and pulse are taken after at least 3 minutes standing, there should be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and increase in heart rate (>20 bpm) (compared to the sitting results) associated with clinical manifestation of postural hypotension. Any subject exhibiting clinical manifestations of postural hypotension should be excluded. 5. Must have haematology, clinical chemistry and urinalysis results at screening that are within the reference range or, if outside the range, not clinically significant as judged by the investigator and confirmed and agreed by the medical monitor; aspartate aminotransferase (AST), ALT and bilirubin must be within the reference range at screening 6. Subjects must: a. Weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18-30 kg/m2. b. Be able to communicate well with the investigator, to understand and comply with the requirements of the study. 7. Good peripheral venous access
Exclusion criteria
1. Known hypersensitivity to any of the study drugs. 2. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations. 3. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes 4. A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at Screening or Baseline: a. PR >210 msec b. QRS complex >120 msec c. QTcF >450 msec or shortened QTcF less than 340 msec or a family history of long QT syndrome or sudden death. d. Second or third degree atrioventricular block. e. Incomplete, full or intermittent bundle branch block. f. Abnormal T wave morphology. 5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 6. Pregnant or nursing (lactating) women. 7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means. 8. Fertile males, defined as all males physiologically capable of conceiving offspring UNLESS the subject agrees to comply with two highly effective contraceptive methods comprising a barrier method (condom) for the entire duration of the study, and twelve weeks following the last study drug administration. Vasectomised males to use a condom for the entire study and 12 weeks following drug administration. 9. Smokers (use of tobacco products in the previous 3 months). Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine greater than or equal to 500 ng/mL. For light smokers (defined as less than 5 cigarettes per day) to pass the cotinine test, smoking should be stopped at least 24 hours prior to reporting to the centre (i.e., Day -2, early morning). Smoking will not be allowed during the study. 10. Use of any prescription drugs, herbal supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing (note that diazepam interferes with the analysis of DSM265 and should not have been used for 8 weeks prior to initial dosing). If needed, (i.e. an incidental and limited need) paracetamol is acceptable up 4 g/day, but must be documented in the Concomitant medications / Significant non-drug therapies page of the CRF. 11. Intake of grapefruit, grapefruit juice or other products containing grapefruit within 14 days of the first drug administration. 12. Excessive intake of caffeine drinks or energy drinks within 48 hours before admission defined as more than three 8 oz. cups of coffee a day, equivalent to roughly 250 mg of caffeine. Defined as 1 (6oz) cup of coffee; 2 cans of cola; 1 (12oz) cup of tea; 3oz milk chocolate. 13. Consumption of broccoli, caviar, sardines, liver, heart and kidneys and yeast supplements one day prior to dosing and throughout the dosing phase. tomatoes and vegemite to be avoided 3 hours prior to dosing and 3 hours post dose. 14. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation. 15. Plasma donation (>100 mL) within 60 days prior to first dosing. 16. Haemoglobin levels below 13.0 g/dL (males) or 11.5 g/dL (females) at screening as determined by Full Blood Cell (FBC) counts. 17. Haptoglobin levels outside reference range for study laboratory. 18. Positive direct antiglobulin test (direct Coomb’s test - DAT). 19. ALT and/or AST and/or lactase dehydrogenase (LDH) should be less than or equal to ULN. 20. Liver enzymes other than ALT, AST, LDH elevated greater than or equal to 1.5xULN within two (2) weeks prior to initial dosing. 21. Recent (within the last three [3] years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.). 22. Recent (within the last three [3] years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). 23. History of any food allergies. 24. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject’s medical history and/or clinical or laboratory evidence of any of the following: i. Inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding in the last 6 months; ii. Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; iii. Pancreatic injury or pancreatitis in the last 6 months; iv. The Investigator should be guided by the following criteria: a. Any single parameter may not exceed 1.5 x upper limit of normal (ULN). A single parameter elevated up to and including 1.5 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrolment/randomisation, to rule out lab error. b. Any elevation of more than one parameter excludes a subject from participation in the study unless otherwise agreed by the medical monitor. Testing may be repeated once more as soon as possible, but in all cases, at least prior to enrolment/randomisation, to rule out lab error. Re-check results must not be clinically significant in order for subject to qualify and confirmed and agreed by the medical monitor. 25. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or urea values, or abnormal urinary constituents (e.g., albuminuria). 26. Evidence of urinary obstruction or difficulty in voiding at screening. 27. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result. 28. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. 29. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and/or baseline.
Outcome results
None listed